Lachmann, in “Theory and Practice of Industrial Pharmacy”, Lea and Febiger, Philadelphia, 2nd Edition, describes that there are three types of fill compositions that can be distinguished with regard to suitability for encapsulation into soft gelatin capsules:                1) Fill compositions whose major ingredients (e.g., excipient or solvent) are water-immiscible substances, such as oil, fat, essential (ethereal) oil, chlorohydrocarbons, esters, ethers, higher alcohols, and organic acids.        2) Fill compositions whose major ingredients are water-miscible, nonvolatile substances, such as polyethylene glycols or emulsifiers.        3) Fill compositions whose major ingredients are water-miscible, relatively volatile substances, such as glycerol, propylene glycol, and benzyl alcohol.        
Fill compositions 2 and 3 are considered to be difficult to encapsulate. For example, Lachmann states that category 3 compositions, particularly those containing more than 5% of water and a low molecular, organic, water-soluble substance (e.g., ethanol, ketones, and amines) can not be encapsultated.
It is known that gels prepared from biological macromolecules (e.g., polysaccharides or proteins) undergo a phenomenon called syneresis. During this process, roughly speaking, a part of the water contained in the gel is forced out of the intermolecular space due to intramolecular and especially intermolecular hydrogen bonds which make macromolecular chains approach one another. As a result of this phenomenon, the water initially contained in the gel is forced out to the physical gel boundaries and passes to the surrounding environment. Soft gelatin capsules (i.e., capsules manufactured on an industrial scale that consist of a shell and a fill composition), wherein the shell is prepared from a gelatin gel and the fill composition contains an active ingredient (e.g., a medicinal, cosmetic, food product, or food additive), also undergo syneresis.
It is very difficult, for the above reasons, to prepare a soft gelatin capsule having a gelatin shell and a fill composition if the fill composition is of type 2 or 3. In addition, it can also be difficult if the fill composition, for reasons mentioned below, is incompatible with the amount of water that passes from the gelatin shell to the contents during the first few hours after encapsulation due to syneresis. Fill types 1 and 2 can be difficult to encapsulate into the gelatin shell due to water incompatibility because of one of the following grounds:                a. The capsule contents (i.e., fill) are hydrophobic and almost entirely immiscible with water. After the contents have been enclosed in a gelatin capsule, the capsule contents separate due to the water passing from the capsule into the contents. The water-insoluble substance can easily crystallize as a result.        b. The contents are hydrophobic (lipophilic) but contain surfactants (tensides), wherein the total HLB value of that composition is such that the composition is capable of absorbing (tolerating) some amount of water. However, the amount of water tolerable is generally less than the amount of water that passes into the contents due to syneresis. Thus, a W/O (water-in-oil) emulsion is produced, and the capsule contents become adversely turbid. The amount of water that passes from the shell to the capsule contents due to syneresis is usually 5 to 15% w/w. Turbidity occurs if the composition of the contents is capable of absorbing no more than 10 and especially no more than 5 wgt % of water without causing phase separation.        c. The contents are lipophilic but contain surfactants (tenides) of such a type and quantity that the contents could tolerate at least 5% or at least 10% w/w of water from syneresis. However, at least one of the essential ingredients of the contents shows such a low solubility in water that the capsules prepared are not stable.        
Solutions for the problems associated with the above types of the contents intended for soft gelatin capsules include the following:                I. For the problem a (i.e., hydrophobic contents), full use is made of their absolute immiscibility with water due to which the aqueous phase that separates after encapsulation can resorb into the gelatin shell during the drying process of capsules. This method of solution is the subject of patent number EP 00671901.        II. For problem b, the amount of water that passes from the shell to the capsule contents is reduced by adding a water-binding substance to the gelatin composition. An example of this method of solution is provided in patent number U.S. Pat. No. 4,804,542. The water-binding substances may be, for instance, starch, cellulose, dry milk, non-hygroscopic mono-, di- and oligo-saccharides, magnesium silicate, silicon dioxide, and their mixtures. Alternatively, the composition can be changed so that the contents are absolutely immiscible with water, and thus transformed into the contents as described in item a) above (e.g., encapsulation of essential oil WO/95/09604, encapsulation of Sandimmun).        III. For problem c, substances are added to increase the water solubility of the essential ingredients of the contents. These substances include, for examples, polyvinyl pyrrolidines (Povidones, Kollidones), polyethoxylated sorbitols, and polyethylene glycols (see EP 0120248 B1).        
There are a number of disadvantages of solutions I-III. First, if a fill composition is transformed into a solution that is totally immiscible with water, as described in solution I, the bioavailability of an active ingredient in the solution usually diminishes. It happens because transport through the intestinal cell membrane is possible only if the immiscible aqueous layer, adjoining the surface of intestinal epithelium and thus forming a hydrophilic barrier to the absorption of lipophilic substances, is permeated through. Second, from a purely practical standpoint, the addition of a water-binding substance to a gelatin composition (solution II) does not solve the problem of a the volume of water that passes from the gelatin gel into the capsule contents due to syneresis as the addition of any such water-binding substance requires the primary amount of water in a gelatin composition to be increased for the processing to be technically feasible. Third, the addition of substances that increase the solubility of a water-insoluble substance in water (solution III) almost always results in interaction with the shell and deterioration of the properties of the contents to be encapsulated.
Lachmann further notes that very low concentrations of hydrophilic surfactants (tensides) of polysorbate or Triton X-100 types can effectively slow down the growth of crystals in water. However, this effect proves to be ineffective with complex systems of the fill compositions intended for soft gelatin capsules. Moreover, the use of macromolecular additives that increase the viscosity of the contents seems to be ineffective as well because a pharmaceutical additive cannot be usually dissolved in the amphiphilic fill composition.
Importantly, the addition of pharmaceutical aids (e.g., solubilizers and surfactants) that increase the solubility of water insoluble substances is not always effective. A notable example of substances, showing such a low solubility in water that the above pharmaceutical aids are ineffective at increasing their water-solubility, are cyclosporines, i.e., cyclic undecapeptides. The pharmaceutical formulations of cyclosporines based on solvent systems consisting of a lipophilic ingredient (e.g., oil ingredient), a solvent (e.g., ethanol), and an amphiphilic ingredient that may have emulsifying properties (e.g., lecithin, and PEG) are characterized by the fact that they are not completely hydrophobic and are not totally immiscible with water. Their HLB value enables water to be absorbed up to a certain limit which is, however, less than the amount of water that passes from the shell to the contents of a gelatin capsule after encapsulation.
Other solutions to the above formulation problems are based on reducing the amount of water that passes to a gelatin composition either by decreasing the gelatin/contents weight ratio during encapsulation (by using the gelatin shell with a thin wall, etc.) or by partially replacing an amount of water in a gelatin composition with a larger amount of a plasticizer (e.g., glycerol, propylene glycol, sorbitol, etc, see GB 2282586), are accompanied by major technological problems. Simple reduction of the primary water content in a gelatin composition results in a necessity of processing a gelatin mixture with very high viscosity which has adverse effects on an encapsulation machine. The replacement of a large amount of water with a plasticizer results in the production of a gelatin mixture from which the strips of gelatin gel are prepared that show high adhesion and low melting point. The use of substances for forming a secondary gel matrix usually leads to the production of very soft capsules that easily fall apart.
It is desirable to find an appropriate substance, which would, at minimum or reasonable concentrations, increase the amount of water that can be absorbed (tolerated) by a composition, without causing phase separation (i.e., turbidity and/or formation of a coarse emulsion and/or crystallization of the water-insoluble component). The finding of an appropriate additive should also provide other benefits in some specific cases. For instance, with the fill compositions containing highly volatile substances, such as ethanol, a very intensive drying process can result in the loss of these volatile substances and a decrease in their concentration in the contents. An adverse consequence of a decrease in the concentration of the volatile substances below a critical limit is the instability of the contents caused by the crystallization of an active substance which was dissolved initially in the volatile substance. The appropriate additive could also help stabilize such compositions.